Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide.

AIMS: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF in patients. METHODS AND RESULTS: We designed a new murine model carrying the Scn5a-M1875T mutation enabling us to study the effects of the Nav1.5 mutation in detail in vivo and in vitro using patch clamp and microelectrode recording of atrial cardiomyocytes, optical mapping, electrocardiogram, echocardiography, gravimetry, histology, and biochemistry. Atrial cardiomyocytes from newly generated adult Scn5a-M1875T+/- mice showed a selective increase in the early (peak) cardiac sodium current, larger action potential amplitude, and a faster peak upstroke velocity. Conduction slowing caused by the sodium channel blocker flecainide was less pronounced in Scn5a-M1875T+/- compared to wildtype atria. Overt hypertrophy or heart failure in Scn5a-M1875T+/- mice could be excluded. CONCLUSION: The Scn5a-M1875T point mutation causes gain-of-function of the cardiac sodium channel. Our results suggest increased atrial peak sodium current as a potential trigger for increased atrial excitability.

Accelerated cortical thinning and volume reduction over time in young people at high genetic risk for bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a familial psychiatric disorder associated with frontotemporal and subcortical brain abnormalities. It is unclear whether such abnormalities are present in relatives without BD, and little is known about structural brain trajectories in those at risk. METHOD: Neuroimaging was conducted at baseline and at 2-year follow-up interval in 90 high-risk individuals with a first-degree BD relative (HR), and 56 participants with no family history of mental illness who could have non-BD diagnoses. All 146 subjects were aged 12-30 years at baseline. We examined longitudinal change in gray and white matter volume, cortical thickness, and surface area in the frontotemporal cortex and subcortical regions. RESULTS: Compared to controls, HR participants showed accelerated cortical thinning and volume reduction in right lateralised frontal regions, including the inferior frontal gyrus, lateral orbitofrontal cortex, frontal pole and rostral middle frontal gyrus. Independent of time, the HR group had greater cortical thickness in the left caudal anterior cingulate cortex, larger volume in the right medial orbitofrontal cortex and greater area of right accumbens, compared to controls. This pattern was evident even in those without the new onset of psychopathology during the inter-scan interval. CONCLUSIONS: This study suggests that differences previously observed in BD are developing prior to the onset of the disorder. The pattern of pathological acceleration of cortical thinning is likely consistent with a disturbance of molecular mechanisms responsible for normal cortical thinning. We also demonstrate that neuroanatomical differences in HR individuals may be progressive in some regions and stable in others.

Differentiating clinical and non-clinical depression: a heuristic study offering a template for extension studies.

OBJECTIVE: To differentiate clinical and non-clinical depression via a set of symptoms. METHODS: A sample of 140 patients attending a clinical service for those with mood disorders together with 40 subjects denying ever experiencing a clinical episode of depression were compared, with participants completing a questionnaire capturing many symptoms of depression as well as illness correlates. RESULTS: A latent class analysis of symptom data identified two classes and with class assignment corresponding strongly with initial clinical vs. non-clinical assignment. Univariate analyses identified the extent to which individual symptoms contributed to differentiation. Study data suggested DSM criteria that would benefit from re-writing or of reassignment. Two models for classifying clinical depression were generated. The first involved individuals feeling hopeless and also being suicidal or at risk of self-harm. The second involved a symptom set corresponding to DSM-5 criteria but with only five making significant independent contributions to diagnostic differentiation. CONCLUSION: The study is heuristic in offering a strategy for more precisely differentiating clinical and non-clinical depression in more representative samples, so allowing resolution of key features, and determining whether a monothetic or polythetic diagnostic symptom criterion model is optimal.

Refined diagnostic criteria for the bipolar disorders: phase two of the AREDOC project.

OBJECTIVE: As limitations exist across DSM criteria sets for defining and differentiating the bipolar disorders generally and their component bipolar I (BP-1) and bipolar II (BP-II) sub-types, we sought to generate empirically based criteria. METHOD: We formed an international Task Force (TF) comprising members with bipolar disorder expertise, and who recruited 74 patients with a TF-diagnosed bipolar I and 104 with a bipolar II condition (with patients responding to definitional queries and symptom questionnaires), while 33 unipolar depressed patients recruited by the first author also completed the symptom questionnaire. A factor analysis sought to determine granular hypo/manic constructs. RESULTS: The bipolar disorder subjects strongly affirmed a new general definition of a bipolar disorder (capturing both manic and hypomanic episodes). While DSM-5 requires impaired functioning, we established that a high percentage of individuals with a BP-I or a BP-II disorder reported improved functioning and therefore modified this criterion. Analyses identified syptoms with differential high rates in individuals with bipolar disorder and its sub-types (and thus not simply capturing happiness), while a factor analysis generated seven symptom constructs both linked with and differing from DSM-5 bipolar symptom criteria. CONCLUSION: This second-stage report details a new set of criteria for differentiating the bipolar disorders from unipolar depressive conditions, while arguing for BP-I and BP-II disorders being differentiated principally by the respective presence or absence of psychotic features. Future studies will evaluate whether further modifications are required and examine for differential treatment benefits for those with a BP-I versus a BP-II condition.

Transverse cardiac slicing and optical imaging for analysis of transmural gradients in membrane potential and Ca2+ transients in murine heart.

KEY POINTS: A robust cardiac slicing approach was developed for optical mapping of transmural gradients in transmembrane potential (Vm ) and intracellular Ca2+ transient (CaT) of murine heart. Significant transmural gradients in Vm and CaT were observed in the left ventricle. Frequency-dependent action potentials and CaT alternans were observed in all ventricular regions with rapid pacing, with significantly greater incidence in the endocardium than epicardium. The observations demonstrate the feasibility of our new approach to cardiac slicing for systematic analysis of intrinsic transmural and regional gradients in Vm and CaT. ABSTRACT: Transmural and regional gradients in membrane potential and Ca2+ transient in the murine heart are largely unexplored. Here, we developed and validated a robust approach which combines transverse ultra-thin cardiac slices and high resolution optical mapping to enable systematic analysis of transmural and regional gradients in transmembrane potential (Vm ) and intracellular Ca2+ transient (CaT) across the entire murine ventricles. The voltage dye RH237 or Ca2+ dye Rhod-2 AM were loaded through the coronary circulation using a Langendorff perfusion system. Short-axis slices (300 µm thick) were prepared from the entire ventricles (from the apex to the base) by using a high-precision vibratome. Action potentials (APs) and CaTs were recorded with optical mapping during steady-state baseline and rapid pacing. Significant transmural gradients in Vm and CaT were observed in the left ventricle, with longer AP duration (APD50 and APD75 ) and CaT duration (CaTD50 and CaTD75 ) in the endocardium compared with that in the epicardium. No significant regional gradients were observed along the apico-basal axis of the left ventricle. Interventricular gradients were detected with significantly shorter APD50 , APD75 and CaTD50 in the right ventricle compared with left ventricle and ventricular septum. During rapid pacing, AP and CaT alternans were observed in most ventricular regions, with significantly greater incidence in the endocardium in comparison with epicardium. In conclusion, these observations demonstrate the feasibility of our new approach to cardiac slicing for systematic analysis of intrinsic transmural and regional gradients in Vm and CaT in murine ventricular tissue.

Long-term clinical impact of permanent cardiac pacing after transcatheter aortic valve implantation with the CoreValve prosthesis: a single center experience.

Aims: To determine the impact of permanent cardiac pacing after transcatheter aortic valve implantation (TAVI) with the CoreValveTM prosthesis in terms of all-cause mortality and morbidity [rehospitalizations for heart failure (HF) or stroke] at the long-term follow-up. Methods and results: The prospective analysis comprised 259 patients (138 women, 53.3%, age 78 ± 6 years) treated by a CoreValveTM prosthesis from April 2008 to December 2015. Forty-two patients were excluded for analysis: 9 with pre-existing permanent pacemaker (PPM) implantation, 19 who required a PPM during the follow-up and 14 patients because of hospital mortality during or after the CoreValveTM prosthesis implantation procedure. The remaining 217 patients were divided in two groups: Group-1 included those patients who required a PPM immediately after TAVI, and Group-2 included those patients who did not require permanent cardiac pacing at the long-term follow-up. Patients received follow-up at 1-month, 6-months, 12-months, and yearly thereafter. A total of 39 patients required a PPM immediately after TAVI (15.0%), but 178 patients (68.7%) did not. The mean follow-up was 37 ± 27 months (range 3-99 months) in both groups. There was no difference between the two groups in terms of all-cause mortality (52.6% vs. 56.8%, P = 0.125; HR 1.22 [0.87-1.77, 95% CI]), or stroke (13.3% vs. 15.1% P = 0.842; HR 1.12 [0.37-3.32, 95% CI]). However, patients who underwent PPM implantation developed an increase in readmissions for HF (21.1% vs. 31.9%, P = 0.015; HR 1.82 [1.23-3.92, 95% CI]). Conclusion: Patients requiring a PPM after TAVI did not have an increase in mortality, or an increase in the likelihood of developing a stroke at a long-term follow-up. However, this subgroup of patients showed an increase in rehospitalization due to HF at medium- and long-term follow-up.

The longitudinal relationship between post-traumatic stress disorder and perceived social support in survivors of traumatic injury.

BACKGROUND: Although perceived social support is thought to be a strong predictor of psychological outcomes following trauma exposure, the temporal relationship between perceived positive and negative social support and post-traumatic stress disorder (PTSD) symptoms has not been empirically established. This study investigated the temporal sequencing of perceived positive social support, perceived negative social support, and PTSD symptoms in the 6 years following trauma exposure among survivors of traumatic injury. METHOD: Participants were 1132 trauma survivors initially assessed upon admission to one of four Level 1 trauma hospitals in Australia after experiencing a traumatic injury. Participants were followed up at 3 months, 12 months, 24 months, and 6 years after the traumatic event. RESULTS: Latent difference score analyses revealed that greater severity of PTSD symptoms predicted subsequent increases in perceived negative social support at each time-point. Greater severity of PTSD symptoms predicted subsequent decreases in perceived positive social support between 3 and 12 months. High levels of perceived positive or negative social support did not predict subsequent changes in PTSD symptoms at any time-point. CONCLUSIONS: Results highlight the impact of PTSD symptoms on subsequent perceived social support, regardless of the type of support provided. The finding that perceived social support does not influence subsequent PTSD symptoms is novel, and indicates that the relationship between PTSD and perceived social support may be unidirectional.

Targeting and transforming major depression.

OBJECTIVE: To detail limitations to the construct of 'major depression', argue for repositioning it as a proxy for 'clinical depression' and then operationalize it and its principal constituent depressive subtypes, while preserving the DSM criteria-based format. METHOD: We summarize limitations to major depression being viewed as a diagnostic entity. Data from 391 clinically depressed patients were analysed to identify high-prevalence non-specific depressive symptoms to define 'clinical depression' as well as the features showing specificity to a melancholic depressive subtype. RESULTS: We identified a set of high-prevalence and generalized symptoms for defining clinical depression and with many being current criteria for major depression. We also developed a refined set of melancholic features and with their underlying distributions generating two classes that correlated strongly with clinical diagnoses of a melancholic or non-melancholic depression, thus validating its capacity to so differentiate. We append criteria sets for diagnosing clinical depression and its principal diagnostic subtypes (psychotic, melancholic and non-melancholic). CONCLUSION: This heuristic study reframes and modifies major depression's criteria set to define a domain of clinical depression with additional criteria and then allowing the delineation of three diagnostic subtypes. If this paradigm shift is accepted and further refined, greater precision in diagnosis, treatment and research would be anticipated.

Interhemispheric white matter integrity in young people with bipolar disorder and at high genetic risk.

BACKGROUND: White matter (WM) impairments have been reported in patients with bipolar disorder (BD) and those at high familial risk of developing BD. However, the distribution of these impairments has not been well characterized. Few studies have examined WM integrity in young people early in the course of illness and in individuals at familial risk who have not yet passed the peak age of onset. METHOD: WM integrity was examined in 63 BD subjects, 150 high-risk (HR) individuals and 111 participants with no family history of mental illness (CON). All subjects were aged 12 to 30 years. RESULTS: This young BD group had significantly lower fractional anisotropy within the genu of the corpus callosum (CC) compared with the CON and HR groups. Moreover, the abnormality in the genu of the CC was also present in HR participants with recurrent major depressive disorder (MDD) (n = 16) compared with CON participants. CONCLUSIONS: Our findings provide important validation of interhemispheric abnormalities in BD patients. The novel finding in HR subjects with recurrent MDD - a group at particular risk of future hypo/manic episodes - suggests that this may potentially represent a trait marker for BD, though this will need to be confirmed in longitudinal follow-up studies.

Neuropsychological and social cognitive function in young people at genetic risk of bipolar disorder.

BACKGROUND: Impairments in key neuropsychological domains (e.g. working memory, attention) and social cognitive deficits have been implicated as intermediate (endo) phenotypes for bipolar disorder (BD), and should therefore be evident in unaffected relatives. METHOD: Neurocognitive and social cognitive ability was examined in 99 young people (age range 16-30 years) with a biological parent or sibling diagnosed with the disorder [thus deemed to be at risk (AR) of developing BD], compared with 78 healthy control (HC) subjects, and 52 people with a confirmed diagnosis of BD. RESULTS: Only verbal intelligence and affective response inhibition were significantly impaired in AR relative to HC participants; the BD participants showed significant deficits in attention tasks compared with HCs. Neither AR nor BD patients showed impairments in general intellectual ability, working memory, visuospatial or language ability, relative to HC participants. Analysis of BD-I and BD-II cases separately revealed deficits in attention and immediate memory in BD-I patients (only), relative to HCs. Only the BD (but not AR) participants showed impaired emotion recognition, relative to HCs. CONCLUSIONS: Selective cognitive deficits in the capacity to inhibit negative affective information, and general verbal ability may be intermediate markers of risk for BD; however, the extent and severity of impairment in this sample was less pronounced than has been reported in previous studies of older family members and BD cases. These findings highlight distinctions in the cognitive profiles of AR and BD participants, and provide limited support for progressive cognitive decline in association with illness development in BD.

Are the bipolar disorders best modelled categorically or dimensionally?

OBJECTIVE: Considerable debate exists as to whether the bipolar disorders are best classified according to a categorical or dimensional model. This study explored whether there is evidence for a single or multiple subpopulations and the degree to which differing diagnostic criteria correspond to bipolar subpopulations. METHOD: A mixture analysis was performed on 1081 clinically diagnosed (and a reduced sample of 497 DSM-IV diagnosed) bipolar I and II disorder patients, using scores on hypomanic severity (as measured by the Mood Swings Questionnaire). Mixture analyses were conducted using two differing diagnostic criteria and two DSM markers to ascertain the most differentiating and their associated clinical features. RESULTS: The two subpopulation solution was most supported although the entropy statistic indicated limited separation and there was no distinctive point of rarity. Quantification by the odds ratio statistic indicated that the clinical diagnosis (respecting DSM-IV criteria, but ignoring 'high' duration) was somewhat superior to DSM-IV diagnosis in allocating patients to the putative mixture analysis groups. The most differentiating correlate was the presence or absence of psychotic features. CONCLUSION: Findings favour the categorical distinction of bipolar I and II disorders and argue for the centrality of the presence or absence of psychotic features to subgroup differentiation.

Are there subtypes of bipolar depression?

OBJECTIVE: To investigate for subtypes of bipolar depression using latent class analysis (LCA). METHOD: Participants were recruited through a bipolar disorder (BD) clinic. LCA was undertaken using: (i) symptoms reported on the SCID-IV for the most severe lifetime depressive episode; (ii) lifetime illness features such as age at first depressive and hypo/manic episodes; and (iii) family history of BD and unipolar depression. To explore the validity of any demonstrated 'classes', clinical, demographic and treatment correlates were investigated. RESULTS: A total of 243 BD subjects (170 with BD-I and 73 with BD-II) were included. For the combined sample, we found two robust LCA solutions, with two and three classes respectively. There were no consistent solutions when the BD-I and BD-II samples were considered separately. Subjects in class 2 of the three-class solution (characterised by anxiety, insomnia, reduced appetite/weight loss, irritability, psychomotor retardation, suicidal ideation, guilt, worthlessness and evening worsening) were significantly more likely to be in receipt of government financial support, suggesting a particularly malign pattern of symptoms. CONCLUSION: Our study suggests the existence of two or three distinct classes of bipolar depression and a strong association with functional outcome.

Differentiating the bipolar disorders from borderline personality disorder.

OBJECTIVE: To identify features differentiating bipolar disorder (BP) from borderline personality disorder (BPD) and with each condition variably defined. METHOD: Participants were assigned a BP or BPD diagnosis on the basis of DSM criteria and, separately, by clinical judgment, and undertook a diagnostic interview and completed self-report measures. RESULTS: Predictors of BPD status varied according to diagnostic decisions, but with the most consistent items being childhood sexual abuse, childhood depersonalization, personality variables relating to relationship difficulties and sensitivity to criticism, and the absence of any BP family history. Across diagnostic groups, personality measure items alone predicted diagnostic allocation with an accuracy of 81-84%, the refined study variables other than hypo/manic features improved the classification rates to 88%, and when the presence or absence of hypo/manic features was added, classification rates increased to 92-95%. CONCLUSION: Study findings indicate that BPD can be differentiated from BP with a high degree of accuracy.

Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression.

OBJECTIVE: This pilot study assessed the feasibility, efficacy and safety of an individual dose-titration approach, and of the intravenous (IV), intramuscular (IM) and subcutaneous (SC) routes for treating depression with ketamine. METHOD: Fifteen treatment-refractory depressed participants received ketamine or midazolam (control treatment) in a multiple crossover, double-blind study. Ketamine was administered by IV (n = 4), IM (n = 5) or SC (n = 6) injection. Dose titration commenced at 0.1 mg/kg, increasing by 0.1 mg/kg up to 0.5 mg/kg, given in separate treatment sessions separated by ≥1 week, with one placebo control treatment randomly inserted. Mood, psychotomimetic and hemodynamic effects were assessed and plasma ketamine concentrations assayed. RESULTS: Twelve participants achieved response and remission criteria, achieved at doses as low as 0.1 mg/kg. All three routes of administration resulted in comparable antidepressant effects. Fewest adverse effects were noted with the SC route. Antidepressant response, adverse effects and ketamine concentrations were dose-related. CONCLUSION: Antidepressant response occurred at a range of doses and at <0.5 mg/kg. The dose-titration approach is a practical method for optimizing the efficacy - side-effects trade-off on an individual patient basis. This pilot study provides preliminary evidence for SC injection as a practical, feasible and efficacious treatment approach.

Assessment of traffic noise levels in urban areas using different soft computing techniques.

Available traffic noise prediction models are usually based on regression analysis of experimental data, and this paper presents the application of soft computing techniques in traffic noise prediction. Two mathematical models are proposed and their predictions are compared to data collected by traffic noise monitoring in urban areas, as well as to predictions of commonly used traffic noise models. The results show that application of evolutionary algorithms and neural networks may improve process of development, as well as accuracy of traffic noise prediction.

Desmopressin improves intestinal functional capillary density and decreases leukocyte activation in experimental endotoxemia.

BACKGROUND: Blood flow to the intestine is decreased in sepsis in favor of vital organs resulting in ischemic damage of the gut mucosa. Once the mucosa is damaged, increased translocation of intestinal bacteria to the systemic circulation may occur. This in turn aggravates the inflammatory response contributing to the development of multi-organ failure. Desmopressin is a synthetic analog of vasopressin, an anti-diuretic hormone which has been shown to induce vasodilation and is thought to be implicated in immunomodulation. In this study, we investigate the effects of desmopressin on the intestinal microcirculation during sepsis in an experimental endotoxemia model in rats using intravital microscopy. In addition, we investigate the effects of desmopressin on systemic inflammation. METHODS: Forty Lewis rats were subdivided into four groups, where rats received intravenous saline (control), desmopressin (1µg/kg/ml), lipopolysaccharide (5mg/kg) or lipopolysaccharide followed by desmopressin. Inflammatory response was assessed by quantifying the number of temporary and firmly adherent leukocytes in submucosal venules. Capillary perfusion was determined by assessing the number of functional, non-functional and dysfunctional capillaries in the intestinal wall layers (muscularis longitudinalis, muscularis circularis and mucosa). Additionally, inflammatory cytokine levels were determined by multiplex assays. RESULTS: The number of firmly adhering leukocytes in V1 venules of rats receiving lipopolysaccharide and treated with desmopressin was significantly reduced compared to lipopolysaccharide only group (LPS: 259±25.7 vs. LPS+DDAVP: 203±17.2; n/mm(2); p<0.05). Additionally, desmopressin treatment improved impaired intestinal microcirculation by improving functional capillary density following lipopolysaccharide administration in all examined layers of the intestinal wall. We also observed a significant decrease in TNF-α levels in rats which received desmopressin in endotoxemia compared to untreated rats (LPS: 383±64.2; LPS+DDAVP: 261.3±22; pg/ml; p<0.05). CONCLUSION: Desmopressin administration improved intestinal capillary perfusion and reduced inflammatory response in rat endotoxemia.

Cleaving depressive diseases from depressive disorders and non-clinical states.

OBJECTIVE: We sought to determine whether putative depressive diseases could be differentiated categorically from clinical depressive disorders and non-clinical mood states. METHOD: We interviewed volunteers who reported or denied any lifetime depressive mood state and analyzed data from the former group reporting on their 'most severe' depressive episode. We employed latent class analysis (LCA) to determine whether a two-class solution was supported and the contribution of individual variables to class allocations. RESULTS: All variables were significant predictors of class allocation. LCA-assigned Class I participants reported more depressive symptoms, had more distressing episodes and more lasting consequences, were more likely to view their depression as 'like a disease', and as being both disproportionately more severe and persistent in relation to any antecedent stressor. Validation involved comparison of LCA assignment with DSM-IV diagnosis for their most severe depressive episode. Of those assigned to Class I, 89% had a DSM diagnosis of melancholic, psychotic or bipolar depression. Class II had all those failing to meet criteria for a depressive episode and the majority of those with a non-melancholic depressive condition. CONCLUSION: Despite not including individual depressive symptoms, study variables strongly differentiated putative depressive diseases from a composite of clinical depressive conditions and subclinical depressive states.

Is essential fatty acid status in late pregnancy predictive of post-natal depression?

OBJECTIVE: We tested the hypothesis that abnormal levels of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) during late pregnancy are associated with antenatal and post-natal depression. METHOD: We interviewed a sample of more than 900 women in late pregnancy. We assessed whether they met criteria for depression on a standardized measure of post-natal depression [the Edinburgh Post-natal Depression Scale (EPDS)] and met DSM-IV criteria for major depression and/or were in receipt of antidepressant medication. Blood was collected at that time to generate data on nine PUFA variables. Sample members were re-interviewed post-natally to determine depressive experience in the 3 months following the birth of their baby. RESULTS: Univariate associations were demonstrated between pre-natal depression categorized using DSM criteria and measures of blood fatty acids including total omega-3, the ratio of omega-6 to omega-3, docosahexaenoic acid (DHA) omega-3 and DHA plus eicosapentaenoic acid (EPA) omega-3. Such associations were not found post-natally, but different associations were quantified between EPDS-diagnosed depression and total omega-6, total omega-3 and EPA omega-3. In multivariate analyses, slight associations were maintained between EPDS and lower omega-3, lower EPA and higher omega-6 when neuroticism, stress during pregnancy, a lifetime episode of depression and older age were included in the analysis. CONCLUSION: Findings in such a large sample indicate that PUFA status in late pregnancy is only slightly linked with the risk of post-natal depression when depression was quantified by the EPDS. There were no associations between post-natal depression diagnosed by DSM criteria and any fatty acid variables.

Short time impact of different hydroxyethyl starch solutions on the mesenteric microcirculation in experimental sepsis in rats.

BACKGROUND: Fluid resuscitation plays a crucial role in the therapy of severe sepsis and septic shock. The use of colloids in sepsis is controversial at present. The aim of our study was to evaluate the effects of second and third generation colloids on the mesenteric microcirculation in early experimental sepsis. METHODS: Male Lewis rats (n=64) were used. Animals underwent sham surgery or colon ascendens stent insertion for sepsis induction by peritonitis. Sixteen hours after the surgery animals were randomly assigned to receive one of the following fluid regimens intravenously: 16ml/kg Ringer's lactate, 64ml/kg Ringer's lactate, 16ml/kg 130/0.4 hydroxyethyl starch, and 16ml/kg 200/0.5 hydroxyethyl starch. Intravital microscopy of the mesenteric microcirculation (plasma extravasation; leukocyte-endothelial interactions) and arterial blood gas analysis were performed before and after fluid resuscitation. RESULTS: In animals with experimental sepsis plasma extravasation was significantly increased compared to control animals (p<0.05). There were no significant differences in plasma extravasation between septic animals receiving crystalloids and or colloid. Furthermore, the type of administered fluid did not influence the number of adhering leucocytes during the observation period. CONCLUSION: The short time impact of different hydroxyethyl starch solutions on the microcirculation of the mesentery is not different from crystalloids in colon ascendens stent peritonitis-induced experimental sepsis in rats.

A randomized controlled trial of mindfulness-based cognitive therapy for bipolar disorder.

OBJECTIVE: To compare the efficacy of mindfulness-based cognitive therapy (MBCT) plus treatment as usual (TAU) to TAU alone for patients with bipolar disorder over a 12-month follow-up period. METHOD: Participants with a DSM-IV diagnosis of bipolar disorder were randomly allocated to either MBCT plus TAU or TAU alone. Primary outcome measures were time to recurrence of a DSM-IV major depressive, hypomanic or manic episode; the Montgomery-Åsberg Depression Rating Scale (MADRS); and Young Mania Rating Scale (YMRS). Secondary outcome measures were number of recurrences, the Depression Anxiety Stress Scales (DASS), and the State Trait Anxiety Inventory (STAI). RESULTS: Ninety-five participants with bipolar disorder were recruited to the study (MBCT = 48; TAU = 47). Intention-to-treat (ITT) analysis found no significant differences between the groups on either time to first recurrence of a mood episode or total number of recurrences over the 12-month period. Furthermore, there were no significant between-group differences on the MADRS or YMRS scales. A significant between-group difference was found in STAI - state anxiety scores. There was a significant treatment by time interaction for the DAS - achievement subscale. CONCLUSION: While MBCT did not lead to significant reductions in time to depressive or hypo/manic relapse, total number of episodes, or mood symptom severity at 12-month follow-up, there was some evidence for an effect on anxiety symptoms. This finding suggests a potential role of MBCT in reducing anxiety comorbid with bipolar disorder.